research methods
& reporting
1
Department of Social Medicine,
University of Bristol, Bristol BS8
2PR
2
MRC Biostatistics Unit, Institute of
Public Health, Cambridge CB2 0SR
3
Clinical Epidemiology and
Biostatistics Unit, Murdoch
Children’s Research Institute, and
University of Melbourne, Parkville,
Victoria 3052, Australia
4
Cancer and Statistical
Methodology Groups, MRC Clinical
Trials Unit, London NW1 2DA
5
Medical Statistics Unit, London
School of Hygiene and Tropical
Medicine London, WC1E 7HT
6
Department of Public Health and
Primary Care, Institute of Public
Health, Cambridge
Correspondence to: J A C Sterne
jonathan.sterne@bristol.ac.uk
Accepted: 30 January 2009
Cite this as: BMJ 2009;338:b2393
doi: 10.1136/bmj.b2393
Multiple imputation for missing data in epidemiological and
clinical research: potential and pitfalls
Jonathan A C Sterne,1 Ian R White,2 John B Carlin,3 Michael Spratt,1 Patrick Royston,4 Michael G Kenward,5
Angela M Wood,6 James R Carpenter5
Most studies have some missing data. Jonathan Sterne and colleagues describe the
appropriate use and reporting of the multiple imputation approach to dealing with them
Missing data are unavoidable in epidemiological and
clinical research but their potential to undermine the
validity of research results has often been overlooked in
the medical literature.1 This is partly because statistical
methods that can tackle problems arising from missing
data have, until recently, not been readily accessible to
medical researchers. However, multiple imputation—a
relatively flexible, general purpose approach to dealing
with missing data—is now available in standard statisti‑
cal software,2‑5 making it possible to handle missing data
semiroutinely. Results based on this computationally
intensive method are increasingly reported, but it needs
to be applied carefully to avoid misleading conclusions.
In this article, we review the reasons why missing data
may lead to bias and loss of information in epidemiologi‑
cal and clinical research. We discuss the circumstances
in which multiple imputation may help by reducing bias
or increasing precision, as well as describing potential
pitfalls in its application. Finally, we describe the recent
use and reporting of analyses using multiple imputation
in general medical journals, and suggest guidelines for
the conduct and reporting of such analyses.
Consequences of missing data
Researchers usually address missing data by including in
the analysis only complete cases —those individuals who
Box 1 | Types of missing data*
• Missing completely at random—There are no systematic
differences between the missing values and the observed
values. For example, blood pressure measurements
may be missing because of breakdown of an automatic
sphygmomanometer
• Missing at random—Any systematic difference between the
missing values and the observed values can be explained
by differences in observed data. For example, missing blood
pressure measurements may be lower than measured blood
pressures but only because younger people may be more
likely to have missing blood pressure measurements
• Missing not at random—Even after the observed data are
taken into account, systematic differences remain between
the missing values and the observed values. For example,
people with high blood pressure may be more likely to miss
clinic appointments because they have headaches
* When one variable has missing data
have no missing data in any of the variables required for
that analysis. However, results of such analyses can be
biased. Furthermore, the cumulative effect of missing
data in several variables often leads to exclusion of a
substantial proportion of the original sample, which in
turn causes a substantial loss of precision and power.
The risk of bias due to missing data depends on the
reasons why data are missing. Reasons for missing data
are commonly classified as: missing completely at ran‑
dom (MCAR), missing at random (MAR), and missing
not at random (MNAR) (box 1).6 This nomenclature
is widely used, even though the phrases convey little
about their technical meaning and practical implica‑
tions, which can be subtle. When it is plausible that
data are missing at random, but not completely at ran‑
dom, analyses based on complete cases may be biased.
Such biases can be overcome using methods such as
multiple imputation that allow individuals with incom‑
plete data to be included in analyses. Unfortunately, it
is not possible to distinguish between missing at ran‑
dom and missing not at random using observed data.
Therefore, biases caused by data that are missing not at
random can be addressed only by sensitivity analyses
examining the effect of different assumptions about the
missing data mechanism.
Statistical methods to handle missing data
A variety of ad hoc approaches are commonly used to
deal with missing data. These include replacing miss‑
ing values with values imputed from the observed data
(for example, the mean of the observed values), using
a missing category indicator,7 and replacing missing
values with the last measured value (last value carried
forward).8 None of these approaches is statistically valid
in general, and they can lead to serious bias. Single
imputation of missing values usually causes standard
errors to be too small, since it fails to account for the
fact that we are uncertain about the missing values.
When there are missing outcome data in a randomised
controlled trial, a common sensitivity analysis is to
explore “best” and “worst” case scenarios by replacing
missing values with “good” outcomes in one group and
“bad” outcomes in the other group. This can be useful if
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RESEARCH METHODS & REPORTING
there are only a few missing values of a binary outcome,
but because imputing all missing values to good or bad
is a strong assumption the sensitivity analyses can give
a very wide range of estimates of the intervention effect,
even if there are only a moderate number of missing
outcomes. When outcomes are quantitative (numerical)
such sensitivity analyses are not possible because there
is no obvious good or bad outcome.
There are circumstances in which analyses of com‑
plete cases will not lead to bias. When missing data
occur only in an outcome variable that is measured
once in each individual, then such analyses will not be
biased, provided that all variables associated with the
outcome being missing can be included as covariates
(under a missing at random assumption). Missing data
in predictor variables also do not cause bias in analyses
of complete cases if the reasons for the missing data are
unrelated to the outcome.9 10 In these circumstances,
specialist methods to address missing data may lessen
the loss of precision and power resulting from exclusion
of individuals with incomplete predictor variables but
are not required in order to avoid bias.
If we assume data are missing at random (box 1),
then unbiased and statistically more powerful analyses
(compared with analyses based on complete cases) can
generally be done by including individuals with incom‑
plete data. Sometimes this is possible by building a more
general model incorporating information on partially
observed variables—for example, using random effects
models to incorporate information on partially observed
variables from intermediate time points11 12 or by using
bayesian methods to incorporate partially observed vari‑
ables into a full statistical model from which the analysis
of interest can be derived.13 Other approaches include
weighting the analysis to allow for the missing data,14 15
and maximum likelihood estimation that simultaneously
models the reasons for missing data and the associations
of interest in the substantive analysis.13 Here, we focus
on multiple imputation, which is a popular alternative
to these approaches.
What is multiple imputation?
Multiple imputation is a general approach to the prob‑
lem of missing data that is available in several com‑
monly used statistical packages. It aims to allow for the
uncertainty about the missing data by creating several
different plausible imputed data sets and appropriately
combining results obtained from each of them.
The first stage is to create multiple copies of the data‑
set, with the missing values replaced by imputed values.
These are sampled from their predictive distribution
based on the observed data—thus multiple imputation
is based on a bayesian approach. The imputation proce‑
dure must fully account for all uncertainty in predicting
the missing values by injecting appropriate variability
into the multiple imputed values; we can never know
the true values of the missing data.
The second stage is to use standard statistical meth‑
ods to fit the model of interest to each of the imputed
datasets. Estimated associations in each of the imputed
datasets will differ because of the variation introduced in
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the imputation of the missing values, and they are only
useful when averaged together to give overall estimated
associations. Standard errors are calculated using Rubin’s
rules,16 which take account of the variability in results
between the imputed datasets, reflecting the uncertainty
associated with the missing values. Valid inferences are
obtained because we are averaging over the distribution
of the missing data given the observed data.
Consider, for example, a study investigating the
association of systolic blood pressure with the risk of
subsequent coronary heart disease, in which data on
systolic blood pressure are missing for some people.
The probability that systolic blood pressure is missing
is likely to decrease with age (doctors are more likely
to measure it in older people), increasing body mass
index, and history of smoking (doctors are more likely
to measure it in people with heart disease risk factors
or comorbidities). If we assume that data are missing
at random and that we have systolic blood pressure
data on a representative sample of individuals within
strata of age, smoking, body mass index, and coronary
heart disease, then we can use multiple imputation to
estimate the overall association between systolic blood
pressure and coronary heart disease.
Multiple imputation has potential to improve the
validity of medical research. However, the multiple
imputation procedure requires the user to model the
distribution of each variable with missing values, in
terms of the observed data. The validity of results from
multiple imputation depends on such modelling being
done carefully and appropriately. Multiple imputation
should not be regarded as a routine technique to be
applied at the push of a button—whenever possible spe‑
cialist statistical help should be obtained.
Pitfalls in multiple imputation analyses
A recent BMJ article reported the development of the
QRISK tool for cardiovascular risk prediction, based
on a large general practice research database.17 The
researchers correctly identified a difficulty with missing
data in their database and used multiple imputation
to handle the missing data in their analysis. In their
published prediction model, however, cardiovascular
risk was found to be unrelated to cholesterol (coded as
the ratio of total to high density lipoprotein cholesterol),
which was surprising.18 The authors have subsequently
clarified that when they restricted their analysis to indi‑
viduals with complete information (no missing data)
there was a clear association between cholesterol and
cardiovascular risk. Furthermore, a similar result was
obtained after using a revised, improved, imputation
procedure.19 It is thus important to be aware of prob‑
lems that can occur in multiple imputation analyses,
which we discuss below.
Omitting the outcome variable from the imputation
procedure
Often an analysis explores the association between
one or more predictors and an outcome but some
of the predictors have missing values. In this case,
the outcome carries information about the missing

values of the predictors and this information must
be used.20 For example, consider a survival model
relating systolic blood pressure to time to coronary
heart disease, fitted to data that have some miss‑
ing values of systolic blood pressure. When missing
systolic blood pressure values are imputed, individu‑
als who develop coronary heart disease should have
larger values, on average, than those who remain
disease free. Failure to include the coronary heart
disease outcome and time to this outcome when
imputing the missing systolic blood pressure values
would falsely weaken the association between systo‑
lic blood pressure and coronary heart disease.
Dealing with non-normally distributed variables
Many multiple imputation procedures assume that
data are normally distributed, so including non-
normally distributed variables may introduce bias.
For example, if a biochemical factor had a highly
skewed distribution but was implicitly assumed to
be normally distributed, then imputation proce‑
dures could produce some implausibly low or even
negative values. A pragmatic approach here is to
transform such variables to approximate normality
before imputation and then transform the imputed
values back to the original scale. Different problems
arise when data are missing in binary or categori‑
cal variables. Some procedures21 may handle these
types of missing data better than others, 13 and this
area requires further research.22 23
Plausibility of missing at random assumption
“Missing at random” is an assumption that justi‑
fies the analysis, not a property of the data. For
example, the missing at random assumption may
be reasonable if a variable that is predictive of miss‑
ing data in a covariate of interest is included in the
imputation model, but not if the variable is omit‑
ted from the model. Multiple imputation analyses
will avoid bias only if enough variables predictive
of missing values are included in the imputation
model. For example, if individuals with high socio‑
economic status are both more likely to have their
systolic blood pressure measured and less likely
to have high systolic blood pressure then, unless
socioeconomic status is included in the model used
when imputing systolic blood pressure, multiple
imputation will underestimate mean systolic blood
pressure and may wrongly estimate the association
between systolic blood pressure and coronary heart
disease.
It is sensible to include a wide range of variables
in imputation models, including all variables in the
substantive analysis, plus, as far as computation‑
ally feasible, all variables predictive of the missing
values themselves and all variables influencing the
process causing the missing data, even if they are
not of interest in the substantive analysis.24 Fail‑
ure to do so may mean that the missing at random
assumption is not plausible and that the results of
the substantive analysis are biased.
research methods & reporting
Data that are missing not at random
Some data are inherently missing not at random
because it is not possible to account for system‑
atic differences between the missing values and
the observed values using the observed data. In
such cases multiple imputation may give mislead‑
ing results. For example, consider a study investi‑
gating predictors of depression. If individuals are
more likely to miss appointments because they are
depressed on the day of the appointment, then it
may be impossible to make the missing at random
assumption plausible, even if a large number of var‑
iables is included in the imputation model. When
data are missing not at random, bias in analyses
based on multiple imputation may be as big as or
bigger than the bias in analyses of complete cases.
Unfortunately, it is impossible to determine from
the data how large a problem this may be. The onus
rests on the data analyst to consider all the possible
reasons for missing data and assess the likelihood of
missing not at random being a serious concern.
Where complete cases and multiple imputation
analyses give different results, the analyst should
attempt to understand why, and this should be
reported in publications.
Computational problems
Multiple imputation is computationally intensive
and involves approximations. Some algorithms
need to be run repeatedly in order to yield adequate
results, and the required run length increases when
more data are missing. Unforeseen difficulties may
arise when the algorithms are run in settings differ‑
ent from those in which they were developed—for
example, with high proportions of missing data,
very large numbers of variables, or small numbers
of observations. These points are discussed more
fully elsewhere.25
Practical implications
The imputation models that were used in the origi‑
nal and revised versions of the QRISK cardiovascu‑
lar risk prediction tool discussed above have been
clarified. 26 The main reasons for the unexpected
finding of a null association between cholesterol
level and cardiovascular risk were omission of the
cardiovascular disease outcome when imputing
missing cholesterol values and calculation of the
ratio of cholesterol to HDL based on imputed cho‑
lesterol and HDL values, which led to extreme val‑
ues of the ratio being included in estimations. The
impact of these pitfalls was increased by the high
proportion of missing data (70% of HDL cholesterol
values were missing).
Reporting in recent literature
Multiple imputation usually involves much more
complicated statistical modelling than the single
regression analyses commonly reported in medi‑
cal research papers. However, constraints on the
length of medical research papers mean that the
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 RESEARCH METHODS & REPORTING

details of the imputation procedures are often partially reported comparisons of distributions of
reported briefly, or not at all. Peer reviewers’ lack key variables in individuals with and without miss‑
of familiarity with multiple imputation may make it ing data. The number of imputation based datasets
difficult for them to ask appropriate questions about was reported in 22 papers. Results of both imputed
the methods employed. and complete cases analyses were fully reported in
To examine recent use and reporting of multiple only seven papers, with one reporting sensitivity
imputation, we searched four major general medi‑ analyses. It was thus rarely possible to assess the
cal journals (New England Journal of Medicine, Lan- impact of allowing for missing data. The variables
cet, BMJ, and JAMA) from 2002 to 2007 for articles used in imputation models were rarely listed, and
reporting original research findings in which multi‑ the plausibility of the missing at random assumption
ple imputation had been used. Articles were located was rarely assessed or discussed.
by using search facilities on each journal’s website to
search for the phrase “multiple imputation” in the Suggested reporting guidelines
full text of all articles published during the speci‑ In the era of online supplements to research papers,
fied period. We found 59 articles, and the reported it is feasible and reasonable for authors to provide
use of multiple imputation roughly doubled over sufficient detail of imputation analyses to facilitate
the six years. peer review, without distracting from the substan‑
The table summarises the results of our survey. tive research question. Box 2 lists the information
Various methods for multiple imputation were that should be provided, either as supplements or
used, with the specific method often reported only within the main paper. This extends guidance pro‑
vaguely (for instance with a book reference). Thirty vided as part of the STROBE initiative to strengthen
six papers reported at least some information on the reporting of observational studies,27 and com‑
the amount of missing data, but only seven fully or plements suggestions for reporting of analyses
using multiple imputation in the epidemiological
Reporting of multiple imputation in 59 papers published in general medical journals from 2002 to ­literature.28
2007* Box 3 relates the suggested guidelines to the use
Reported characteristic No of papers of multiple imputation in a published paper that
Amount of missing data examined the cost effectiveness of chemotherapy
No 23 with that of standard palliative care in patients with
Partially 6 advanced non-small cell lung cancer.
Yes 30
Comparison of distribution of key variables in individuals with and without missing data
Summary
No 52
We are enthusiastic about the potential for multi‑
Partially 2
ple imputation and other methods14 to improve the
Yes 5
No of imputations
validity of medical research results and to reduce the
No 35
waste of resources caused by missing data. The cost
Yes 22 of multiple imputation analyses is small compared
Unclear† 2 with the cost of collecting the data. It would be a pity
Results if the avoidable pitfalls of multiple imputation slowed
Both multiple imputation and complete case results tabulated 7 progress towards the wider use of these methods. It
Multiple imputation results tabulated: is no longer excusable for missing values and the
  Complete case results not reported 28 reason they arose to be swept under the carpet, nor
  Complete case results in text 1 for potentially misleading and inefficient analyses of
  Complete case results stated to be similar 2 complete cases to be considered adequate. We hope
Complete case results tabulated:
that the pitfalls and guidelines discussed here will
  Multiple imputation results not reported‡ 1
contribute to the appropriate use and reporting of
  Multiple imputation results in text 4
methods to deal with missing data.
  Multiple imputation results stated to be similar 11
  Stated no significant difference from multiple imputation 4
We thank Lucinda Billingham for checking our description of the article
described in box 3.
  Sensitivity analysis done 1
Contributors: JACS, IRW, JBC, and JRC wrote the first draft of the paper.
Variables used in imputation
MS conducted the review of the use of multiple imputation in medical
No 53
journals and analysed the data. All authors contributed to the final draft and
No but normality discussed 1 subsequent redrafts of the paper. JACS, IRW, and JRC will act as guarantors
Yes 5 Funding: Funded by UK Medical Research Council grant G0600599. IRW
Plausibility of the missing at random assumption was supported by MRC grant U.1052.00.006 and JBC by NHMRC (Australia)
No 56 grant 334336.
Invalid discussion 2 Competing interests: None declared.
Yes (sensitivity analysis) 1 Provenance and peer review: Not commissioned; externally peer
*One paper that used multiple imputation to conduct sensitivity analyses rather than to deal with missing data was
reviewed.
excluded from the table. 1 Wood A, White IR, Thompson SG. Are missing outcome data
† Both papers used hotdeck imputation. One referred to a paper on multiple imputation but gave no further details, adequately handled? A review of published randomised
the other stated that “1000 imputation sequences” were used. controlled trials. Clin Trials 2004;1:368-76.
‡The methods section reports that a range of multiple imputation techniques were used to assess the robustness 2 Royston P. Multiple imputation of missing values. Stata J
and sensitivity of conclusions, but no results are reported. 2004;4:227-41.

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Box 2 | Guidelines for reporting any analysis potentially affected by missing data
• Report the number of missing values for each variable of interest, or the number of cases
with complete data for each important component of the analysis. Give reasons for
missing values if possible, and indicate how many individuals were excluded because
of missing data when reporting the flow of participants through the study. If possible,
describe reasons for missing data in terms of other variables (rather than just reporting a
universal reason such as treatment failure)
• Clarify whether there are important differences between individuals with complete and
incomplete data—for example, by providing a table comparing the distributions of key
exposure and outcome variables in these different groups
• Describe the type of analysis used to account for missing data (eg, multiple imputation),
and the assumptions that were made (eg, missing at random)
For analyses based on multiple imputation
• Provide details of the imputation modelling:
• Report details of the software used and of key settings for the imputation modelling
• Report the number of imputed datasets that were created (Although five imputed
datasets have been suggested to be sufficient on theoretical grounds,10 11 a larger
number (at least 20) may be preferable to reduce sampling variability from the
imputation process29)
• What variables were included in the imputation procedure?
• How were non-normally distributed and binary/categorical variables dealt with?
• If statistical interactions were included in the final analyses, were they also included
in imputation models?
• If a large fraction of the data is imputed, compare observed and imputed values
• Where possible, provide results from analyses restricted to complete cases, for
comparison with results based on multiple imputation. If there are important differences
between the results, suggest explanations, bearing in mind that analyses of complete
cases may suffer more chance variation, and that under the missing at random
assumption multiple imputation should correct biases that may arise in complete cases
analyses
• Discuss whether the variables included in the imputation model make the missing at
random assumption plausible
• It is also desirable to investigate the robustness of key inferences to possible departures
from the missing at random assumption, by assuming a range of missing not at random
mechanisms in sensitivity analyses. This is an area of ongoing research30 31
Box 3 | Example of use of multiple imputation
Burton et al32 used data from a randomised controlled trial to compare the cost
effectiveness of chemotherapy with that of standard palliative care in patients with
advanced non-small cell lung cancer. Costs were obtained for a subset of 115 patients but
were complete for only 82 patients.
They gave the extent and distribution of missing data in table 1 of their paper. Patient
and tumour characteristics were stated to be comparable in those with complete and
incomplete data, but the effect of treatment on survival was stated to differ. The authors
used the multiple imputation procedure in SAS statistical software (PROC MI) to impute
the missing data. Variables included in the imputation models were listed. Five imputed
datasets were created. A total run length of 12 500 iterations was used with imputations
made after every 2500th imputation. Log and logit transformations were used to deal
with non-normality, and a two stage procedure was used to deal with variables with
a high proportion of zero values (semicontinuous distributions). Complete data were
transformed back to their original scales before analysis.
The complete case analysis resulted in a higher mean cost for chemotherapy compared
with palliative care (£2804 (€3285; $4580), 95% confidence interval £1236 to £4290)
than did the analyses using multiple imputation (£2384, 95% CI £833 to £3954). The
complete case analyses implied that chemotherapy was not cost effective (mean net
monetary benefit −£3346), but the multiple imputation analyses implied that it was cost
effective (mean net monetary benefit £1186), although confidence intervals were wide.
In the discussion, the authors noted the multiple imputation analysis “assumes that
the incomplete cost data are missing at random such that the missingness of the cost
components are associated only with the observed data, either the observed covariates
or effectiveness.” They did not, however, discuss whether the missing at random
assumption was plausible or conduct sensitivity analyses investigating the robustness of
the findings to assumed missing not at random mechanisms.
research methods & reporting
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